Certain 2,5-diazabicyclo[4.2.0]octanes and octahydrofuro[3,4-b]pyrazines as glp-1 receptor modulators

Abstract

There are disclosed certain 2,5-diazabicyclo[4.2.0]octanes of formula (I) and octahydrofuro[3,4-b]pyrazines, and pharmaceutically acceptable salts thereof, together with compositions containing them and their use in therapy. The compounds are GLP-1 receptor modulators and are thereby particularly useful in the treatment or prophylaxis of cardiovascular disease and metabolic conditions, for example Type 2 diabetes.

1 . A compound of Formula (I), 
       
         
           
           
               
               
           
         
       
       or a compound of Formula (II), 
       
         
           
           
               
               
           
         
         wherein 
         A is phenyl or pyridyl; 
         X is independently N or C, provided that no more than two atoms in the aromatic ring B are N; 
         Z 1  is N or CR 3 ; 
         Z 2  and Z 3  are each independently N or CR 4 , provided that when Z 1  or Z 3  is N, Z 2  is CR 4 ; 
         R 1  is independently selected from F, Cl, Br, CN, OCH 3 , OCFH 2 , OCF 2 H, OCF 3 , CH 3 , CFH 2 , CF 2 H and CF 3 ; 
         R 2  is selected from F, Cl or CN; 
         R 3  is selected from H, F, Cl, N(CH 3 ) 2 , C 1-2 alkyl and OC 1-2 alkyl, wherein said C 1-2 alkyl is substituted by 0, 1, 2 or 3 F; 
         R 4  is independently selected from H, F, Cl, OH, CH 3 , CFH 2 , CF 2 H, CF 3 , OCH 3 , OCFH 2 , OCF 2 H and OCF 3 ; 
         R 5  is selected from (4- to 6-membered)heterocycloalkyl, (5- to 6-membered)heteroaryl, CN, C 1-4 alkyl, O(C 1-4 alkyl), S(C 1-4 alkyl), cyclopropyl, cyclobutyl, O(cyclopropyl) or S(cyclopropyl), wherein said (4- to 6-membered)heterocycloalkyl and (5- to 6-membered)heteroaryl is substituted by 0 or 1 substituent selected from C 1-2 alkyl and wherein said C 1-4 alkyl is substituted by 0 or 1 substituent selected from CN or OCH 3 , and 0, 1, 2 or 3 F and wherein said cyclopropyl and cyclobutyl is substituted by 0 or 1 substituent selected from CN, OCH 3 , OCFH 2 , OCF 2 H, OCF 3  and CH 2 CN and 0, 1, 2 or 3 F; 
         R 6  is independently selected from F, C 1-2 alkyl and OC 1-2 alkyl, wherein said C 1-2 alkyl is substituted by 0, 1, 2 or 3; 
         m is 0, 1, 2 or 3; 
         n is 0 or 1; 
         p is 1, 2 or 3; and 
         q is 0, 1 or 2; 
         or a pharmaceutically acceptable salt thereof. 
       
     
     
         2 . The compound according to  claim 1  of Formula (Ia) 
       
         
           
           
               
               
           
         
         or Formula (IIa), 
       
       
         
           
           
               
               
           
         
         wherein 
         A is phenyl or pyridyl; 
         X is N or C; 
         R 1  is independently selected from F, Cl, Br, CN, OCH 3 , OCFH 2 , OCF 2 H, OCF 3 , CH 3 , CFH 2 , CF 2 H and CF 3 ; 
         R 2  is selected from F, Cl or CN; 
         R 3  is selected from H, F, Cl, N(CH 3 ) 2 , C 1-2 alkyl and OC 1-2 alkyl, wherein said C 1-2 alkyl is substituted by 0, 1, 2 or 3 F; 
         R 4  is independently selected from H, F, Cl, OH, CH 3 , CFH 2 , CF 2 H, CF 3 , OCH 3 , OCFH 2 , OCF 2 H and OCF 3 ; 
         R 5  is selected from (4- to 6-membered)heterocycloalkyl, (5- to 6-membered)heteroaryl, CN, C 1-4 alkyl, O(C 1-4 alkyl), S(C 1-4 alkyl), cyclopropyl, cyclobutyl, O(cyclopropyl) or S(cyclopropyl), wherein said (4- to 6-membered)heterocycloalkyl and (5- to 6-membered)heteroaryl is substituted by 0 or 1 substituent selected from C 1-2 alkyl and wherein said C 1-4 alkyl is substituted by 0 or 1 substituent selected from CN or OCH 3 , and 0, 1, 2 or 3 F and wherein said cyclopropyl and cyclobutyl is substituted by 0 or 1 substituent selected from CN, OCH 3 , OCFH 2 , OCF 2 H, OCF 3  and CH 2 CN and 0, 1, 2 or 3 F; 
         m is 0, 1, 2 or 3; 
         n is 0 or 1; 
         p is 1, 2 or 3; and 
         q is 0, 1 or 2; 
         or a pharmaceutically acceptable salt thereof. 
       
     
     
         3 . The compound according to  claim 1 , wherein
 A is phenyl;   X is N;   R 1  is independently selected from F, Cl and CN;   R 2  is selected from F, Cl or CN;   R 3  is selected from H, F, Cl, N(CH 3 ) 2 , C 1-2 alkyl and OC 1-2 alkyl, wherein said C 1-2 alkyl is substituted by 0, 1, 2 or 3 F;   R 4  is independently selected from H, F, Cl, OH, CH 3  and OCH 3 ;   R 5  is selected from (4- to 6-membered)heterocycloalkyl, (5- to 6-membered)heteroaryl, CN, C 1-4 alkyl, O(C 1-4 alkyl), S(C 1-4 alkyl), cyclopropyl, cyclobutyl, O(cyclopropyl) or S(cyclopropyl), wherein said (4- to 6-membered)heterocycloalkyl and (5- to 6-membered)heteroaryl is substituted by 0 or 1 substituent selected from C 1-2 alkyl and wherein said C 1-4 alkyl is substituted by 0 or 1 substituent selected from CN or OCH 3 , and 0, 1, 2 or 3 F and wherein said cyclopropyl and cyclobutyl is substituted by 0 or 1 substituent selected from CN, OCH 3 , OCFH 2 , OCF 2 H, OCF 3  and CH 2 CN and 0, 1, 2 or 3 F;   m is 0, 1 or 2;   n is 0 or 1; and   p is 1, 2 or 3;   or a pharmaceutically acceptable salt thereof.   
     
     
         4 . The compound according to  claim 1  selected from:
 2-(((1R,6S)-5-(6-((4-Cyano-2-fluorobenzyl)oxy)pyridin-2-yl)-2,5-diazabicyclo[4.2.0]octan-2-yl)methyl)-1-((1-methyl-1H-pyrazol-3-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid, 
 2-(((1R*,6S*)-5-(6-((4-Cyano-2-fluorobenzyl)oxy)pyridin-2-yl)-2,5-diazabicyclo[4.2.0]octan-2-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid, 
 2-(((1R*,6R*)-5-(6-((4-Cyano-2-fluorobenzyl)oxy)pyridin-2-yl)-2,5-diazabicyclo[4.2.0]octan-2-yl)methyl)-4-fluoro-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid, 
 2-(((1R*,6R*)-5-(6-((4-Cyano-2-fluorobenzyl)oxy)pyridin-2-yl)-2,5-diazabicyclo[4.2.0]octan-2-yl)methyl)-4-methoxy-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid, 
 2-(((1R*,6R*)-5-(6-((4-Cyano-2-fluorobenzyl)oxy)pyridin-2-yl)-2,5-diazabicyclo[4.2.0]octan-2-yl)methyl)-5-fluoro-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid, 
 rel-4-Chloro-2-(((1R,6S)-5-(6-((4-cyano-2-fluorobenzyl)oxy)pyridin-2-yl)-2,5-diazabicyclo[4.2.0]octan-2-yl)methyl)-1-(((R)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid, 
 rel-5-Chloro-2-(((1R,6S)-5-(6-((4-cyano-2-fluorobenzyl)oxy)pyridin-2-yl)-2,5-diazabicyclo[4.2.0]octan-2-yl)methyl)-1-(((R)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid, 
 rel-7-Chloro-2-(((1R,6S)-5-(6-((4-cyano-2-fluorobenzyl)oxy)pyridin-2-yl)-2,5-diazabicyclo[4.2.0]octan-2-yl)methyl)-1-(((R)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid, 
 2-(((1R*,6R*)-5-(6-((4-Chloro-2-fluorobenzyl)oxy)pyridin-2-yl)-2,5-diazabicyclo[4.2.0]octan-2-yl)methyl)-4-methoxy-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid, 
 rac-1-(2-(tert-Butoxy)ethyl)-2-(((1R,6S)-5-(6-((4-cyano-2-fluorobenzyl)oxy)pyridin-2-yl)-2,5-diazabicyclo[4.2.0]octan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid, 
 rac-1-(2-Butoxyethyl)-2-(((1R,6S)-5-(6-((4-cyano-2-fluorobenzyl)oxy)pyridin-2-yl)-2,5-diazabicyclo[4.2.0]octan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid, 
 rel-2-(((1R,6R)-5-(6-((4-Chloro-2-fluorobenzyl)oxy)pyridin-2-yl)-2,5-diazabicyclo[4.2.0]octan-2-yl)methyl)-1-((1-ethyl-1H-imidazol-5-yl)methyl)-4-methoxy-1H-benzo[d]imidazole-6-carboxylic acid, 
 rac-2-(((1R,6S)-5-(6-((4-Cyano-2-fluorobenzyl)oxy)pyridin-2-yl)-2,5-diazabicyclo[4.2.0]octan-2-yl)methyl)-1-((5-methylisoxazol-3-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid, 
 rac-2-(((1R,6S)-5-(6-((4-Cyano-2-fluorobenzyl)oxy)pyridin-2-yl)-2,5-diazabicyclo[4.2.0]octan-2-yl)methyl)-1-((4-methylpyridin-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid, 
 2-(((4aRS,7aSR)-4-(6-((4-Chloro-2-fluorobenzyl)oxy)pyridin-2-yl)hexahydrofuro[3,4-b]pyrazin-1(2H)-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid, 
 2-(((4aR*,7aS*)-4-(6-((4-Chloro-2-fluorobenzyl)oxy)pyridin-2-yl)hexahydrofuro[3,4-b]pyrazin-1(2H)-yl)methyl)-4-methoxy-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid, 
 2-(((4aRS,7aSR)-4-(6-((4-Cyano-2-fluorobenzyl)oxy)pyridin-2-yl)hexahydrofuro[3,4-b]pyrazin-1(2H)-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid, 
 rel-2-(((4aR,7aS)-4-(6-((4-Chloro-2-fluorobenzyl)oxy)pyridin-2-yl)hexahydrofuro[3,4-b]pyrazin-1(2H)-yl)methyl)-4-fluoro-1-(((S)-tetrahydrofuran-3-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid, 
 2-(((4aR*,7aS*)-4-(6-((4-Chloro-2-fluorobenzyl)oxy)pyridin-2-yl)hexahydrofuro[3,4-b]pyrazin-1(2H)-yl)methyl)-4-fluoro-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid, 
 rel-2-(((4aR,7aS)-4-(6-((4-Chloro-2-fluorobenzyl)oxy)pyridin-2-yl)hexahydrofuro[3,4-b]pyrazin-1(2H)-yl)methyl)-1-(oxazol-4-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid, 
 rel-2-(((4aR,7aS)-4-(6-((4-Chloro-2-fluorobenzyl)oxy)pyridin-2-yl)hexahydrofuro[3,4-b]pyrazin-1(2H)-yl)methyl)-1-(pyridin-3-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid, 
 4-Chloro-2-(((4aR*,7aS*)-4-(6-((4-chloro-2-fluorobenzyl)oxy)pyridin-2-yl)hexahydrofuro[3,4-b]pyrazin-1(2H)-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid, 
 rel-2-(((4aR,7aS)-4-(6-((4-Chloro-2-fluorobenzyl)oxy)pyridin-2-yl)hexahydrofuro[3,4-b]pyrazin-1(2H)-yl)methyl)-4-fluoro-1-(2-(2-methyl-1H-imidazol-1-yl)ethyl)-1H-benzo[d]imidazole-6-carboxylic acid, 
 rel-4-Chloro-2-(((4aR,7aS)-4-(6-((4-chloro-2-fluorobenzyl)oxy)pyridin-2-yl)hexahydrofuro[3,4-b]pyrazin-1(2H)-yl)methyl)-1-(2-(2-methyl-1H-imidazol-1-yl)ethyl)-1H-benzo[d]imidazole-6-carboxylic acid, and 
 rel-2-(((4aR,7aS)-4-(6-((4-Chloro-2-fluorobenzyl)oxy)pyridin-2-yl)hexahydrofuro[3,4-b]pyrazin-1(2H)-yl)methyl)-1-(2-(2-methyl-1H-imidazol-1-yl)ethyl)-1H-benzo[d]imidazole-6-carboxylic acid, 
 
       or a pharmaceutically acceptable salt thereof. 
     
     
         5 . (canceled) 
     
     
         6 . A pharmaceutical composition comprising a compound according to  claim 1 , or a pharmaceutically acceptable salts thereof, in admixture with a pharmaceutically acceptable adjuvant, diluent or carrier. 
     
     
         7 . A method of treating, or reducing the risk of, cardiovascular disease or metabolic conditions which comprises administering to a person suffering from or at risk of, said disease or condition, a therapeutically effective amount of a compound according to  claim 1 , or a pharmaceutically acceptable salt thereof. 
     
     
         8 . The method according to  claim 7 , wherein said disease is type 2 diabetes. 
     
     
         9 - 10 . (canceled)